Short-term adverse effects of COVID-19 vaccines after the first, second, and booster doses: a cross-sectional survey from Punjab, Pakistan, and the implications

ABSTRACT Background: Safety and efficacy concerns regarding coronavirus disease 2019 (COVID-19) vaccines are common among the public and have a negative impact on their uptake. We aimed to report the adverse effects currently associated with the vaccine in Pakistan to build confidence among the population for its adoption. Methods: A cross-sectional study was conducted in five districts of the Punjab province of Pakistan between January and March 2022. The participants were recruited using convenience sampling. All data were analyzed using SPSS 22. Results: We recruited 1622 people with the majority aged between 25-45 years. Of these, 51% were female, including 27 pregnant women and 42 lactating mothers. Most participants had received the Sinopharm (62.6%) or Sinovac (17.8%) vaccines. The incidences of at least one side effect after the first (N = 1622), second (N = 1484), and booster doses (N = 219) of the COVID-19 vaccine were 16.5%, 20.1%, and 32%, respectively. Inflammation/erythema at the injection site, pain at the injection site, fever, and bone/muscle pain were common side effects of vaccination. No significant differences were observed in the adverse effect scores between all demographic variables except for pregnancy (P = 0.012) after the initial dose. No significant association was observed between any variable and the side effect scores of the second and booster doses of the vaccine. Conclusions: Our study showed a 16-32% prevalence of self-reported side effects after the first, second, and booster COVID-19 vaccinations. Most adverse effects were mild and transient, indicating the safety of different COVID-19 vaccines.


INTRODUCTION
Since World War II, the coronavirus pandemic has arguably been humanity's greatest challenge. It has killed millions of people and severely impacted the economies of countries worldwide 1,2 . Pakistan, a low-middle-income country, has been significantly affected by the coronavirus disease 2019 (COVID-19) 3,4 . A vaccination campaign was initiated by the government on February 2, 2021 to curb the spread of COVID-19 in Pakistan 5 . The first phase targeted frontline health care workers (HCWs) 5 . Afterward, the government in Pakistan started mass vaccination campaigns by establishing multiple vaccine centers in every district of the country in hospitals and public places. It introduced a field force to help optimize the vaccination program. Subsequently, individuals above 60 years of age were vaccinated for free to increase the vaccination rates 6 . Vaccination efforts were then focused on the remaining population. Currently, all individuals aged >12 years are able to receive COVID-19 vaccines 7 . A variety of such vaccines are now available at vaccination centers in Pakistan. These include mRNA vaccines: Moderna and Pfizer-BioNTech; inactivated vaccines: Sinopharm and Sinovac; and non-replicating viral vector-based vaccines: AstraZeneca, CanSino/PakVac, and Sputnik 7 .
Moreover, booster doses of COVID-19 vaccines are also available for free to immunocompromised individuals, HCWs, and the public 8 . This is because most of the population cannot afford the vaccine. The safety and efficacy of all COVID-19 vaccines mentioned above have been established in clinical trials 9 . With the considerable efforts of the Government of Pakistan, 71.62% of the country's population has been fully vaccinated, and 75.68% of the population has received at least one dose as of November 7, 2022 10 .
The efficacy of the COVID-19 vaccine and its contribution to herd immunity are well-established in the literature [11][12][13][14] . This is important in countries like Pakistan, which are under extreme pressure because of the economic consequences of public health measures, including lockdown measures, implemented to reduce the spread of COVID-19 and its consequences on morbidity and mortality in the absence of effective vaccines [15][16][17] .
Vaccine hesitancy is common in Pakistan. It may impede mass immunization against COVID-19 despite the government's initiation of an aggressive and comprehensive vaccination campaign with the establishment of vaccination centers in every town/locality [18][19][20][21][22][23] . Several factors contribute to vaccine hesitance, including conspiracy theories and mistrust of health authorities regarding the safety of vaccines 20,21,24 . Widespread speculation regarding serious adverse events following immunization 20,25 and false news circulating on social media further undermine the COVID-19 vaccination campaign 22,26 .
Successful vaccination campaigns require fundamental queries related to vaccine safety and efficacy to be fully addressed to increase the willingness of the population to receive COVID-19 vaccines 22,27 . In many parts of the world, the adverse effects of COVID-19 vaccines have been reported alongside reports of their efficacy in preventing severe illness, morbidity, and mortality 9,28-31 . However, only a few studies on the possible adverse effects of COVID-19 vaccines have been reported in Pakistan 32,33 . Consequently, we conducted this study to evaluate possible adverse events after the first, second, and booster doses of COVID-19 vaccines in Pakistan. This is important because early studies involving fewer patients typically do not sufficiently report adverse events. Therefore, coupled with concerns among the population regarding the speed of developing vaccines against COVID-19, post-vaccination monitoring of side effects is important to address any negative perceptions regarding COVID-19 vaccines, including misinformation. Such information is also important for health authorities and public health policymakers as they seek to improve acceptance rates because of the efficacy of the vaccines.

Study design, participants, and setting
A cross-sectional study design was implemented to collect information on the adverse effects of COVID-19 vaccines. Data were gathered from the general population of Punjab between January and March 2022, and participants were recruited through convenience sampling in public locations.

Inclusion and exclusion criteria
Participants had to be >12 years, have received at least one dose of any COVID-19 vaccine in Pakistan, and be willing to participate in the survey. We excluded those who had not received any COVID-19 vaccine or refused to participate in the study.

Study instrument
The instrument used in this study was adopted from a previous study conducted in Jordan 34 with slight modifications after receiving appropriate permission from the corresponding author and reviewing the literature 25,[28][29][30][31][32][33] . The leading investigators (ZUM and MS) prepared the initial draft of the study instrument. This draft was evaluated by a team of experts from the fields of medicine and pharmacy to determine the understanding and clarity of the content of the study tool. The data collection tool was revised based on the recommendations of the expert panel. The final draft of the study instrument comprised the following four sections: Section I contained seven questions about patient demographics, including sex, marital status, age, level of education, presence of any chronic disease, allergy to any food or medicine, and current status of influenza vaccination.
Section II discussed the current status and types of COVID-19 vaccines administered.
Section III comprised a list of possible adverse effects of COVID-19 vaccines, and participants were requested to select those they have experienced following COVID-19 vaccination. Hospitalizations due to adverse effects and the time of onset were also recorded.
Section IV presented information on the management of adverse events. This included the duration of symptoms and medication administration for any side effects encountered, which were subsequently recorded.

Data collection procedure
The data-collection team administered questionnaires at different public locations. The investigators invited the general public to participate in the study after explaining the study objectives. Members of the data collection team interviewed those willing to participate. Children's data were collected from their parents/guardians, and personal information was not collected from participants.

Ethical consideration
All participants provided written informed consent prior to their enrollment in the study. For children (aged <18 years), consent was obtained from their parents before data collection. The participant's data were coded and stored in a password-protected file accessible only to the researchers. The Human Research Ethics Committee of the Department of Pharmacy Practice, University of Lahore, approved this study (REC/DPP/FOP/UOL/68).

Data analysis
The SPSS version 22.0 for Windows was used for analyzing the data in this study. Categorical variables are presented as numbers and percentages, whereas continuous variables are presented as medians (interquartile ranges) and/or means (standard deviations). Adverse effect scores were calculated by adding the number of adverse effects reported by the study participants. The scores were subsequently compared between the demographic variables using the Mann-Whitney and Kruskal-Wallis tests 35 , where applicable. The aforementioned non-parametric tests ranked all values from low to high and compared the mean ranks. Statistical significance was set at P < 0.05.

Characteristics of the sample population
The investigators approached 1877 participants, of whom 1622 individuals were included in the study (response rate: 86.4%). Table 1 shows the demographic details of the sample population. Most of the study participants were aged 25-45 years, followed by 46-79 years (27.3%). Of these, 51% (N = 824) participants were females, including 27 pregnant females and 42 lactating mothers. Most of the study participants (33.2%) had a primary level of education, followed by 27.3% with a secondary education. Most patients (92%) had no underlying diseases or illnesses. Among those with comorbidities (N = 125), diabetes mellitus, arterial hypertension, and heart disease were the top three. None of the study participants reported being vaccinated against influenza. As shown in Table 1, most participants were immunized against COVID-19 with Sinopharm (62.6%) and Sinovac (17.8%). In the study population, 7% individuals did not complete the COVID-19 vaccination course. Furthermore, of the 1515 individuals who completed immunization, 219 received a booster dose of the COVID-19 vaccine (187 homologous and 32 heterologous booster shots). Figure 1 shows that the incidences of at least one side effect after the first (N = 1622), second (N = 1484), and booster doses (N = 219) of the COVID-19 vaccine were 16.5%, 20.1%, and 32%, respectively. In most cases, the onset of side effects was within 24 h (Figure 2). Table 2 shows the complete side effect profiles of the COVID-19 vaccines. The respondents reported 28 different side effects after receiving the first vaccination and 16 after the second vaccination. Six side effects were observed after administration of the booster dose of the COVID-19 vaccine.

Incidence of side effects post-Covid-19 vaccination
The most common side effects after the first dose were inflammation or erythema at the injection site, pain at the injection site, fever, and bone and muscle pain. Similarly, inflammation or erythema at the injection site (10.4%), fever (3.6%), and pain at the injection site (3.3%) were the most frequently reported adverse effects of the second dose. However, patients who received a booster vaccine reported muscle and bone pain (22.8%), fatigue (17.8%), and fever (4.1%) within a day of receiving the booster dose ( Table 3).

Self-reported COVID-19 status
No, I have never been infected with COVID-19 1501 (92.5) Yes, I got infected before receiving the vaccine 121 (7.5)      The maximum number of side effects reported after the first, second, and booster vaccinations were four (mean = 0.21 ± 0.52), five (mean = 0.21 ± 0.45), and three (0.47 ± 0.78), respectively. No significant difference (P > 0.05) was observed in the side effect scores between all demographic variables except for pregnancy (P = 0.012), with pregnant women reporting more side effects with the COVID-19 vaccines after receiving the initial dose. We also found no significant difference in adverse effect scores between those who reported having COVID-19 before receiving the vaccine and those who did not (P = 0.457). No significant association was observed between any variable and the side-effect score following the second or booster doses of the vaccine.

Need for hospitalization due to side effects associated with COVID-19 vaccination
Only five (0.3%) participants reported being hospitalized due to side effects after the first dose, while hospitalization due to side effects of the vaccine after the second and booster doses was 0.1% and 0.5%, respectively. Table 3 shows the details of the adverse effects of hospitalization.

Medications used to manage side effects of COVID-19 vaccines
The percentages of patients requiring medication to manage side effects after the first, second, and booster doses were 3.8% (N = 62), 2% (N = 30), and 15.1% (N = 33), respectively. Of the medicines prescribed to treat side effects, acetaminophen and non-steroidal anti-inflammatory drugs were the most common.

DISCUSSION
Our study revealed that most of the study population received the Sinopharm vaccine, followed by the Sinovac vaccine. This is because most of the imported COVID-19 vaccines were from China to initiate the COVID-19 vaccine program. In later stages, additional COVID-19 vaccines, including Pfizer-BioNTech, AstraZeneca, and Moderna vaccines, were imported from other countries under the Covax initiatives 33 . It was encouraging that most of the study population did not experience any adverse effects following the different COVID-19 vaccines. Inflammation and erythema at the injection site, followed by injection site pain, were the most common local adverse effects reported by those who received the primary COVID-19 vaccination series. The most frequent systemic adverse effects were fever and arthralgia/myalgia. The most frequent adverse effects of booster vaccinations were arthralgia/ myalgia, fatigue, and fever. Our findings corroborate the results of clinical trials of various COVID-19 vaccines, most of which were administered to our study population. In the phase I/II trial of the Sinopharm vaccine, the most common adverse reactions were pain and fever, reported in a small number of vaccine recipients 36 . Furthermore, in phase III trials, most adverse events were mild to moderate in severity, with common adverse events such as pain at the injection site, headache, and fatigue 37,38 . In the combined safety profile of phase I and phase II trials of Sinovac, any adverse event within 28 days after injection occurred in 26% of participants in the 1.5 μg group, 29% in the 3 μg group, and 24% in the placebo group, without a significant difference (P > 0.05) 39 . Injection site pain was the most commonly reported local adverse event (1.5 μg group: 16%; 3 μg group: 16%; placebo group: 2%; P < 0.001), followed by inflammation at the injection site (1.5 μg group: 1%; 3 μg group: 3%; placebo group: 1%; P = 0.50). The most frequently reported systemic adverse effect was fever 39 . Sinovac's phase III trial revealed that the frequency of any adverse event following immunization was 18.9%, compared with 16.9% in the placebo group (P = 0.018) 40 . In the clinical trial, the most frequent local adverse event associated with this vaccine was injection site pain, followed by erythema. However, the most common systemic adverse events were fatigue, headache, and myalgia 40 . In the randomized, placebo-controlled, observer-blinded trial of the BNT162b2 vaccine (Pfizer-BioNTech), the safety profile was characterized by transient mild-to-moderate injection-site pain, fatigue, and headache 41 . The incidence of severe adverse reactions was low and similar in vaccine and placebo recipients.
The similarity of the results is encouraging and should provide reassurance to the population of Pakistan.

Strengths and limitations
Our study had several limitations. We conducted this study in only five districts in Punjab. However, this province currently comprises over 50% of the population of Pakistan, and these districts were carefully chosen as representatives of Punjab. We recruited study participants through convenience sampling; consequently, there was a risk of bias inherent to this non-probability sampling technique. Additionally, the side effects were self-reported; therefore, participants' information may have reporting and/or recall bias. Another important limitation was the high variability in the frequency of COVID-19 vaccines. It would have been ideal to compare the safety of the vaccines; however, this was not possible considering the different vaccines purchased by the Government of Pakistan.
Furthermore, the main aim of this study was to reassure patients about the safety profile of the vaccines, given the current hesitancy rates and their rationale. We acknowledge that the number of people who received a booster vaccine was quite small in our study (N = 219), and it would be of great interest to conduct a large-scale study to compare the side effects associated with the first, second, and booster doses of COVID-19 vaccines in Pakistan. We will follow up on this topic. Despite these limitations, we believe that the findings of our study are encouraging and will help the general population build greater trust in the safety of COVID-19 vaccines in Pakistan to enhance future vaccination rates.
In conclusion, a low prevalence of adverse effects was generally observed among COVID-19 vaccine recipients in Pakistan. Most side effects (either local or systemic) were mild and transient. These findings indicate the short-term safety of COVID-19 vaccines for boosting purposes. This should help enhance future vaccination rates.

ACKNOWLEDGMENTS
Authors are grateful to the study participants for sparing their time to take part in this study. All the authors, in particular, Dr. Muhammad Salman (former employee at the UOL), are grateful to the members of the Ethical Committee, Department of Pharmacy Practice, Faculty of Pharmacy, UOL to improve protocol of the present research.